Diagnosis and therapy of tuberculous meningitis in children

Diagnosis and therapy of tuberculous meningitis in children
Department of Maternal and Pediatric Sciences, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico,Via Commenda 9, 20122 Milan, Italy
Children are among the subjects most frequently affected by tuberculous meningitis (TBM) due to their
relative inability to contain primary Mycobacterium tuberculosis infection in the lung. TBM is a devas-
tating disease with about 30% mortality among the most severe cases; moreover, 50% of survivors have
neurological sequelae despite an apparently adequate administration of antibiotics. Early diagnosis and
prompt treatment are crucial for reducing the risk of a poor outcome. However, especially in children, thebest and most rapid way to conﬁrm the diagnosis is controversial; the optimal choice, dose, and treat-
ment duration of anti-tuberculosis drugs are not precisely deﬁned, and the actual importance of
adjunctive therapies with steroids and neurosurgery has not been adequately demonstrated. This review
is an effort to discuss present knowledge of the diagnosis and treatment of pediatric TBM in order to offer
the best solution to address this dramatic disease. In conclusion, we stress that new studies in children
are urgently needed because data in the early years of life are more debatable than those collected inadults. In the meantime, when treating a child with suspected TBM, the most aggressive attitude todiagnosis and therapy is necessary, because TBM is a devastating disease.
Ó 2012 Elsevier Ltd. All rights reserved.
present knowledge on the diagnosis and treatment of pediatricTBM in order to offer the best solution to address this dramatic
Tuberculous meningitis (TBM) occurs mainly in developing
countries where tuberculosis (TB) is more common and the widerincidence of the human immunodeﬁciency virus (HIV) favors the
onset of a great number of cases. However, TBM is also encounteredin industrialized countries, particularly in recent years, as a conse-
Although early and rapid identiﬁcation of TBM is crucial for
quence of the large immigration of infected and the
successful disease management, in most of the cases, diagnosis is
frequent use of biological agents that favor TB dev
signiﬁcantly delayed. Initial signs and symptoms of disease are
Children are among the subjects who most frequently suffer from
non-speciﬁc and the suspicion of TBM usually arises only some days
TBM due to their relative inability to contain primary Mycobacte-
or weeks after the disease’s onset and is not different in children
rium tuberculosis infection in the lung.TBM is a devastating
who have or have not been vaccinated with Bacille Calmette-Gue-
disease with about 30% mortality in the most severe forms;
Fever, headache, anorexia, and vomiting characterize the
moreover, 50% of survivors have neurological sequelae despite
prodrome of disease in older children, whereas failure to thrive,
apparently adequate administration of antibiotics.Early diag-
poor appetite, vomiting, and sleep disturbances are more common
nosis and prompt treatment are crucial for reducing the risk of
in younger TBM is more easily suspected when these
a negative evolution. However, especially in children, the best and
symptoms are associated with a history of recent contact with
most rapid way to diagnose the disease is controversial; the
a case of documented TB or when, after the ﬁrst days of disease,
optimal choice, dose, and treatment duration of anti-tuberculosis
relevant neurological manifestations, such as cranial nerve palsy,
drugs are not precisely deﬁned, and the actual importance of
adjunctive therapies with steroids and neurosurgery have not beenadequately demonstrated. Consequently, the approach to pediatric
TBM is frequently inadequate. This review is aimed at discussing
Diagnosis of probable or possible TBM requires signs and
symptoms of meningitis in association with clinical, CSF and cerebral
* Corresponding author. Tel.: þ39 02 55032203; fax: þ39 02 50320206.
imaging ﬁndings suggestive of M. tuberculosis infection. The
1472-9792/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
N. Principi, S. Esposito / Tuberculosis 92 (2012) 377e383
evidence of TB outside the CNS can further contribute to probable or
a predominance of lymphocytes, an increase in protein content and
possible diagnosis. A score that includes the most common ﬁndings
a very low glucose concentration. These ﬁndings are different from
in children with TBM and in which single ﬁndings are assigned
those usually reported for typical bacterial meningitis in which CSF
a point according to the frequency with which they are usually
is opaque, pleocytosis is very high, and neutrophils are predomi-
demonstrated has been created by Marais et According to these
nant. Reduction in glucose content is usually less marked in
authors, probable TBM is deﬁned by a score between 10 and 12,
comparison to purulent bacterial meningitis, where CSF glucose
whereas possible TBM is deﬁned by a score higher than 6 ().
values below 5 mg/dL will often be found. Clear appearance, whiteblood cell count between 50 and 500 per mL with 50% or more
lymphocytes, protein content greater than 1 g/L and a glucose
The low sensitivity and speciﬁcity of most of the relevant
content less than 2.2 mmol/L are considered to be indicative of
neurologic symptoms has been largely demonstrated by several
TBM. However, atypical CSF ﬁndings have been repeatedly
clinical trials. Prodromal stage 7 days, optic atrophy on fundal
examination, focal deﬁcit and abnormal movements were found to
To improve diagnosis of probable or possible TBM, other CSF
be independently predictive of TBM (p < 0.007) in a group of chil-
tests have been recently studied. Among them, the evaluation of
dren aged 1 months to 12 ybut optic atrophy is usually a late
occurrence and abnormal movements are rare.
interferon-gamma (IFN-g) release by lymphocytes, the detection ofM. tuberculosis antigens and antibodies, and the immunocyto-
chemical staining of mycobacterial antigens (ISMA) in the cyto-
CSF modiﬁcations are common in children with TBM. In these
plasm of CSF macrophages are those for which the greatest amount
cases, CSF shows a clear appearance, moderate pleocytosis with
of data is available. However, none of these seems to have elevatedsensitivity and speciﬁcity, although they can be useful in somecases to support the diagnosis.
Table 1Diagnostic criteria for classiﬁcation of deﬁnite, probable or possible tuberculous
The ADA activity test is a rapid test that represents the prolif-
eration and differentiation of lymphocytes as a result of the acti-vation of cell-mediated immunity after M. tuberculosis infection.
It has given good results in the diagnosis of the pleural, peritoneal
and pericardial forms of tuberculosis. When applied to patients
with TBM, it was found that ADA activity could not distinguish
between TBM and other types of bacterial meningitis, but that it
could add useful information to suggest TBM once meningitis due
to different pathogens has been ruled out. ADA values from 1 to 4 U/
L (sensitivity >93% and speciﬁcity <80%) can help to exclude TBM
and values >8 U/L (sensitivity <59% and speciﬁcity >96%) can
improve the diagnosis of TBM (p < 0.001). However, values
between 4 and 8 U/L are insufﬁcient to conﬁrm or exclude the
diagnosis of TBM (p ¼ 0.07).Moreover, false positive results can
Measurement of IFN-g release by lymphocytes stimulated by
M. tuberculosis antigens has been demonstrated to be more accu-
rate than skin testing for the diagnosis of latent TB and to be useful
in the diagnosis of extrapulmonary TB. However, sensitivity and
speciﬁcity of the test varied markedly according to the disease
siteWhen adapted to TBM, collected data vary sharply from study
to study. Liao et al. found that the test was 100% sensitive and 100%
speciﬁc,whereas other authors reported a very poor value of the
test in diagnosing It has been suggested that the failure of
the test in some studies could be ascribed to the fact that
lymphocytes die rapidly when stimulated with M. tuberculosis
antigens ex vivo so that the test can be negative even if TBM is
Detection of various M. tuberculosis antigen markers, such as
lipoarabinomannan, puriﬁed protein derivatives, heat shock
protein of 62Kd and 14Kd, GroE, Ag 85 complex and 38Kd antigen,
have been tried to conﬁrm TBM However, their
presence remains questionable and many of these antigens are
reported in blood only, but not in the CSF and this questions their
veracity for the diagnosis of TBM. The same seems true for speci
M. tuberculosis cultured from another source
Use of ISMA in the cytoplasm of CSF macrophages is based on
(i.e., sputum, lymph node, gastric lavage,
the assumption that, during the initial stage of infection, ingestion
of the bacilli by macrophages takes place and that during the
second stage bacilli grow logarithmically within newly recruitedmacrophages.Consequently, the positivity of the test indicates
CNS, central nervous system; CT, computed tomography; MR, magnetic resonance;
that viable M. tuberculosis isolates are present in CSF. A recent study
NAAT, nucleic acid ampliﬁcation test; TB, tuberculosis.From Marais et al.,modiﬁed.
in which this test was evaluated in 393 patients, among whom
N. Principi, S. Esposito / Tuberculosis 92 (2012) 377e383
some with deﬁnite TBM, has demonstrated that it has a sensitivity
attempt to standardize clinical case deﬁnition of TBM for use in
of 73.5% and speciﬁcity of 90.7% with positive and negative
predictive values of 52.9% and 96.0% respectivelyThis means that
However, all the methods for the conﬁrmation of the diagnosis
this test can be useful, in actual fact, to exclude TBM, but that its
of TBM risk further delay in diagnosis and initiation of therapy.
sensitivity is too low to diagnose deﬁnite TBM.
Culture requires >2e3 weeks to give results. Moreover, bothmicroscopic AFB detection and culture isolation have low sensi-
tivity, particularly in children in whom these allow for identiﬁca-
Similarly to clinical and laboratory ﬁndings, cerebral imaging
tion of only about 20% of cases. Finally, modern molecular methods
can also contribute to diagnosing probable or possible TBM.
can have, at the same time, both low sensitivity and low speciﬁcity.
However, discrimination between TBM and another cerebral
Sensitivity of traditional microbiological tests seems to be strictly
disease is frequently very difﬁcult. The most common brain
dependent on the amount of CSF that is sampled, the frequency of
computed tomography (CT) or magnetic resonance (MR) features in
LPs, the time devoted to the microscopic search for the organism,
children with TBM are hydrocephalus, which can be demonstrated
and the moment in which the CSF is drawn. The minimum volume
in about 80% of cases,and basal meningeal enhancement, found
of CSF to obtain reliable results seems to be 6 mL,an amount
in 75% of young patients.Infarction, as a result of ongoing
difﬁcult to be safely obtained in younger children that have a low
vasculitis, particularly of the basal ganglia and of the areas of the
total volume of CSF.In comparison with a single LP, four LPs can
medial striates and thalamoperforating arteries, and tuberculoma
increase sensitivity of microscopy examination and culture from
can be found in a smaller number of TBM pediatric cases.MR
37% and 52% to 87% and 83%, respectively.However, in pediatrics
has a higher sensitivity than CT in the identiﬁcation of CNS modi-
several lumbar punctures are not easily performed, mainly because
ﬁcation, although it does not seem to offer more help in dis-
of the aversion of parents to let their children undergo repeated
tinguishing TBM from other CNS diseases such as viral encephalitis,
invasive procedures. Thirty minutes are considered the minimum
cryptococcal meningitis or cerebral lymphomas that can have
time needed for a correct evaluation of CSF by microscopand in
similar cerebral imaging.However, a combination of basal
a busy laboratory this may not be possible. Finally, antibiotic
meningeal enhancement, infarction and hydrocephalus was found
administration rapidly reduces the number of pathogens in the CSF.
to have a high speciﬁcity for the diagnosis of TBM, whereas basal
Anti-tuberculosis drugs are usually started immediately after TBM
meningeal enhancement was reported as the most sensitive
is suspected and consequently LPs are negative even in children
feature.Recently, it was reported that border zone necrosis (BZN)
actually suffering from the disease.
of the brain parenchyma in areas adjacent to meningeal inﬂam-
Accuracy of nucleic acid-based ampliﬁcation (NAA) tests,
mation can occur in 50% of children with Detection and
though better than that of conventional microscopic
conﬁrmation of cytotoxic edema associated with BZN using
was not considered completely satisfactory for many years
diffusion-weighted MR can offer further support to probable or
possible TBM diagnosis. However, it has to be highlighted that in
M. tuberculosis, in comparison with culture, ranged from 2% to 100%
stage 1 TBM imaging ﬁndings may be normal, yet it is at that stage
and from 75% to 100%, respectively.The most important reason
that treatment should be started in order to prevent brain damage.
for the low sensitivity of some of the ﬁrst polymerase chain reac-tion (PCR)-based methods was the use of a single target for
ampliﬁcation. Most studies have used the IS6110 gene ofM. tuberculosis that is usually present in multiple copies in the
The evidence of TB infection or disease outside the CNS can
bacterial genome assuring high sensitivity. Unfortunately, this gene
signiﬁcantly increase the probability or possibility that a child with
is absent in a signiﬁcant number of isolates, so that a false negative
cerebral signs and symptoms can have TBM. However, a great
result was regularly found when patients infected by these isolates
number of patients, especially when HIV negative, will present
were More reliable results have been obtained in more
with normal chest radiography or negative tuberculin skin
recent years when ampliﬁcation of multiple gene targets from CSF
testiMoreover, particularly in high TB prevalence areas,
samples was performed. Kusum et al. evaluated a multiplex PCR
a positive skin test with an unrelated illness has been frequently
using protein b, MPB64 and IS6110 primers and found that this
documented. Taking samples from sites of frequent TB infection
method had a sensitivity of 94.4% and a speciﬁcity of 100% in
such as lymph nodes, lung and gastric ﬂuid can increase the like-
culture-conﬁrmed Recently, molecular methods capable of
lihood of a positive culture. Gastric aspiration was positive in 68% of
simultaneously identifying both M. tuberculosis and resistance of
the strain to antibiotics have been developed. Among these, the
In conclusion, considering the need for a rapid diagnosis of TBM,
Xpert M. tuberculosis/RIF assay seems to be the most promising,
all possible efforts to demonstrate the probable or possible pres-
although no data regarding its use in extrapulmonary TB are
ence of this disease must be pursued using all available laboratory
available.Finally, preliminary studies have suggested that
tests and imaging techniques. Moreover, the potential severity of
molecular methods could be used to quantify the bacterial load in
TBM calls for the immediate treatment of all the doubtful cases.
CSF and consequently to evaluate treatment response.
In conclusion, making a deﬁnite diagnosis of TBM is still
a problem. In many cases, diagnosis remains probable or possibleand treatment is initiated without the demonstration of the pres-
Independently from the characteristics and duration of the
prodromal stage, a deﬁnite diagnosis of TBM can be made onlywhen, after a lumbar puncture (LP) in a patient with signs andsymptoms of central nervous system (CNS) disease, acid-fast bacilli
(AFB) are seen and/or M. tuberculosis is detected by molecularmethods and/or cultured in cerebrospinal ﬂuid (CSF). The same
Treatment of TBM is based on three different components:
conclusion can be drawn from autopsy when M. tuberculosis is
administration of anti-infective drugs active against M. tuberculosis,
identiﬁed in histological lesions of the CNS. This is in line with what
modulation of the destructive elements of the immune response,
has been deﬁned by most of the authors who have made the
and management of increased intracranial pressure.
N. Principi, S. Esposito / Tuberculosis 92 (2012) 377e383
Table 3Recommended daily dosages of second-line anti-tuberculous drugs for treatment oftuberculous meningitis in infants and children.
Contrary to what applies to pulmonary tuberculosis, recom-
mendations for anti-infective therapy in TBM are, in general, not
based on well-conducted clinical trials. Few data, particularly in
children, are available to guide the clinician who derives the
schemes for treatment of TBM from those used for pulmonary TB.
10e15 mg/kg/24 h (max 1 g/day) orallyas a single daily dose
This explains why most experts recommend that the treatment of
TBM follows the model of short-course chemotherapy with an
intensive phase of treatment with several drugs followed by
15e30 mg/kg/24 h (max 1000 mg) orallyas a single daily dose
summarizes the main guidelines for treatment of pedi-
atric TBM and shows second-line drugs that could be used
in case of resistant strains taking in account that very few data of
their real efﬁcacy, safety and tolerability in children are available.
7.5e10 mg/kg/24 h (max 500 mg) orallyas a single daily dose
Before the emergence of multidrug-resistant M. tuberculosis, three
drugs were considered adequate for the ﬁrst phase. More recently,
in order to address the problem of resistance, four antibiotics for
the initial months of treatment are preferred. However, there is no
agreement on the duration of each of the two phases and on thetotal length of therapy. The intensive phase can range from 2 to 6
considered second-line drugs because of their toxicity.However,
months and total treatment from 6 months to one yearUnfor-
when TBM has to be treated ETH and cycloserine that have
tunately, studies comparing the different schemes of antibiotic
a reasonable CSF penetration, even better of that of EBM can be
administration in children are not available.Studies regarding
considered where they are available.Newer anti-tuberculosis
the outcome of 6-month regimens have demonstrated that the
drugs, such as ﬂuoroquinolones, have been scarcely used in pedi-
relapse rate was not signiﬁcantly different from that reported when
atric TBM and are off-label in children, although for both penetra-
longer periods of antibiotic administration were used.This seems
tion in CSF and in-vitro efﬁcacy against M. tuberculosis, they are
to speak in favor of the shortest therapy. However, because most of
these data have been collected in adults, no deﬁnitive conclusions
Independently from the drugs prescribed, the scheme of admin-
can be drawn when children with TBM have to be treated.
istration used, and the total duration of therapy, INH remains the drug
According to Donald, in situations where the directly observed
most widely prescribed in children for initial TBM treatment.The
treatment and follow-up after treatment completion is impeccable,
choice of INH is based on several positive factors: the good absorption
a 6-month treatment duration is probably satisfactory.When
by the gastrointestinal tract, the rapid diffusion in body compart-
treatment supervision and/or follow-up are questionable, it may be
ments including CSF and the low toxicity. Moreover, it rapidly kills
better practice to prolong length of treatment.
most of the replicating M. tuberculosis and, consequently, protects
For several years now, the drugs considered essential by the
companion drugs against the development of resistance, reduces the
World Health Organization (WHO) to treat pulmonary TB in chil-
risk of infecting contacts and leads to a more rapid mitigation of
dren are isoniazid (INH), rifampicin (RMP),pyrazinamide (PZA), and
disease symptoms. In children, INH is recommended at the dose of
ethambutol Other drugs, such as streptomycin (SM) or
10 mg/kg/day (range: 6e15 mg/kg/day, maximum 500 mg), generally
other aminoglycosides, ethionamide (ETH) and cycloserine are
useful to reach in CSF concentrations that are high enough to elimi-nate fully sensitive M. tuberculosis or resistant mutants with a rela-tively low minimum inhibitory concentration (MIC) even in patients
who are fast acetylatorsWhen M. tuberculosis resistance is sus-
Main guidelines for the treatment of tuberculous meningitis in infants and children.
pected or demonstrated, the highest doses have to be administered,striking the right balance between toxicity and optimal ef
Isoniazid 10e20 mg/kg/24 h (max 500 mg) orally for 12 months
RMP has the advantage of killing low or non-replicating
Rifampin 10e20 mg/kg/24 h (max 600 mg) orally for 12 months
M. tuberculosis, thus complementing INH activity and allowing
Pyrazinamide 30e35 mg/kg/24 h (max 2 g) orally for 2 months
the sterilization of lesions. Unfortunately, it has several limits
Ethambutol 15e20 mg/kg/24 h (max 1 g) orally for 2 months
because its concentrations in CSF do not exceed 10% of those in
Prednisolone 4 mg/kg/24 h orally for 4 weeks, followed by a
its absorption is negatively inﬂuenced by food andantacidsand it has a relevant protein binding action that can
American Thoracic Society, CDC, and Infectious Diseases Society of America
ﬁcantly reduce its clinical efﬁcacy.RMP is ofﬁcially recom-
e15 mg/kg/24 h (max 300 mg) orally for 9e12 months
Rifampin 10e20 mg/kg/24 h (max 600 mg) orally for 9e12 months
mended at the dose of 10e20 mg/kg/daybut, considering the
Pyrazinamide 15e30 mg/kg/24 h (max 2 g) orally for 2 months
MIC of susceptible M. tuberculosis and the concentrations reached
Ethambutol 15e20 mg/kg/24 h (max 1 g) orally for 2 months
in CSF of it has been recommended to administer the
Dexamethasone 8 mg/day/24 h orally for children weighing less than 25 kg
highest dosage in young children and infants <10 kg and at least
and 12 mg/day for children weighing 25 kg or more for 3 weeks,
15 mg/kg/day in older patients weighing between 10 and 20
followed by a reducing course over 3 weeks
The dose of 10 mg/kg/day could lead to CSF levels <1.0 mg/mL,
which is ineffective against most M. tuberculosis, particularly when
Isoniazid 10e15 mg/kg/24 h (max 300 mg) orally for 6 monthsRifampin 10e20 mg/kg/24 h (max 600 mg) orally for 6 months
strains with increased MIC are present. However, raising the dose
Pyrazinamide 15e30 mg/kg/24 h (max 2 g) orally for 2 months
has no effect on highly resistant mutants as their MIC is far too high.
Streptomycin 20e40 mg/kg (max 1 g) i.m. or i.v. for 2 months
For the early phase of therapy, PZA and any of the second-line
Prednisone 2 mg/kg/24 h orally for 4 weeks, followed by a
drugs are usually administered. PZA has a good penetration in
CSF and, despite a very low early bactericidal activity in the ﬁrst
N. Principi, S. Esposito / Tuberculosis 92 (2012) 377e383
days of treatment, it is important because in the course of time it
the severity of increased intracranial preShunting is
becomes as effective as INH and RMP.Moreover, together with
RMP, it makes an essential contribution to the sterilization of
communicating or when medical treatment fails even if it is not
lesions and has an important role in reducing the risk of recur-
known which kind of shunting is the In communicating
rence.PZA is recommended at the dose of 30e35 mg/kg/daily
hydrocephalus, diuretics are generally effective in reducing the risk
with the highest dosage for younger children. With these regimens,
of long-term neurologic impairment. Endoscopic third ven-
CSF concentration in excess of 20 mg/mL higher than the MIC of PZA
triculostomy is considered a possible option, particularly in patients
who have experienced multiple episodes of shunt dysfunct
The fourth drug to complete the antibiotic regimen in the early
phase of TBM therapy is usually chosen from EMB or SM. Both have
limited CSF penetration, low bactericidal activity and do notcontribute to the sterilization of lesions and reduction of the risk of
Despite undeniable advances in the identiﬁcation of markers of
relapse. Their contribution to the treatment of TBM is probably
deﬁnite, probable or possible TBM have been made in recent years,
minor, although they protect companion drugs against the emer-
most of the problems that pediatricians and neurologists have to
face in TBM are still unsolved. The most important difﬁculty regards
The growing emergence of resistant strains has raised the
early diagnosis because in those patients in whom TBM is sus-
question of the importance of resistance to TBM outcome. Available
pected early enough present treatment is sufﬁcient to bring about
data clearly indicate that resistance to both INH and RMP signiﬁ-
complete cure in the majority of cases, at least when pathogens are
cantly worsen the ﬁnal outcome.The effect of resistance to
fully drug susceptible and treatment is complied with. More difﬁ-
a single drug is more controversial. Regarding INH, some studies
culties in achieving cure can arise when treatment is delayed and
indicate that INH resistance does not inﬂuence TBM outcome,
when multidrug-resistant pathogens are the cause of the disease. In
whereas other studies seem to associate INH resistance to a signif-
this case prognosis is poor, particularly in children because it is not
icant higher risk of death.These different ﬁndings may be due to
deﬁnitively clear what has to be done when resistance of
different doses of INH used and different resistant mutants.
M. tuberculosis to one or more antibiotics is present, which duration
However, in order to minimize risks, it has been suggested that
of treatment is to be recommended and what is the actual role of
duration of treatment for TBM caused by INH-resistant organisms
adjunctive therapy. New studies in children are urgently needed. In
should be extended and always include PZA as well as a new anti-
the meantime, when treating a child with suspected TBM, the most
aggressive attitude is to be used both for diagnosis and for therapy,because TBM is an extremely devastating disease.
This study was supported by a grant from the Italian
In meningitis, most of the damage derives from the immune
Ministry of Health (Bando Giovani Ricercatori 2007).
response elicited by the presence of bacterial pathogens in theCNS.This leads to a very relevant inﬂammatory process with
The authors have no conﬂict of interest
signiﬁcant inﬁltrative, proliferative and necrotizing vessel pathol-
ogies.Anti-tuberculous chemotherapy and the administration ofthalidomide and salicylates appear to be relatively ineffective in
preventing vascular complications that remain the major unre-
Committee of Fondazione IRCCS Ca’ Granda Ospedale Maggiore
solved problem related to TBM. Corticosteroids have been used in
Policlinico, Milan, Italy and all the papers included in this review
TBM for over 50 years, although the real importance of these drugs
have been approved by local Ethical Committees.
in this disease is not completely deﬁned. A meta-analysis recentlycarried out that comprised 7 randomized controlled trials involvinga total number of 1140 participants, both children and adults, has
demonstrated that in HIV-negative subjects prednisolone or
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